title: Estrogen represses gene expression through reconfiguring chromatin structures.
abstract: Estrogen regulates over a thousand genes, with an equal number of them being induced or repressed. The distinct mechanisms underlying these dual transcriptional effects remain largely unknown. We derived comprehensive views of the transcription machineries assembled at estrogen-responsive genes through integrating multiple types of genomic data. In the absence of estrogen, the majority of genes formed higher-order chromatin structures, including DNA loops tethered to protein complexes involving RNA polymerase II (Pol II), estrogen receptor alpha (ERα) and ERα-pioneer factors. Genes to be 'repressed' by estrogen showed active transcription at promoters and throughout the gene bodies; genes to be 'induced' exhibited active transcription initiation at promoters, but with transcription paused in gene bodies. In the presence of estrogen, the majority of estrogen-induced genes retained the original higher-order chromatin structures, whereas most estrogen-repressed genes underwent a chromatin reconfiguration. For estrogen-induced genes, estrogen enhances transcription elongation, potentially through recruitment of co-activators or release of co-repressors with unique roles in elongation. For estrogen-repressed genes, estrogen treatment leads to chromatin structure reconfiguration, thereby disrupting the originally transcription-efficient chromatin structures. Our in silico studies have shown that estrogen regulates gene expression, at least in part, through modifying previously assembled higher-order complexes, rather than by facilitating de novo assembly of machineries.
authors.affiliation: Department of Biomedical Informatics, University of Pittsburgh, Pittsburgh, PA, USA, Department of Computer Science, University of Pittsburgh, Pittsburgh, PA, USA, Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA, Women's Cancer Research Center, University of Pittsburgh, Pittsburgh, PA, USA, Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA and Fondazione Ri.MED, Palermo, Italy.
authors.forename: Hatice Ulku
authors.initials: HU
authors.lastname: Osmanbeyoglu
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Lu
authors.forename: Steffi
authors.initials: S
authors.lastname: Oesterreich
authors.forename: Roger S
authors.initials: RS
authors.lastname: Day
authors.forename: Panayiotis V
authors.initials: PV
authors.lastname: Benos
authors.forename: Claudia
authors.initials: C
authors.lastname: Coronnello
authors.forename: Xinghua
authors.initials: X
authors.lastname: Lu
mesh_terms: D002843:Chromatin / Q000737:chemistry* / Q000378:metabolism; D003198:Computer Simulation; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D002843:Chromatin; D047628:Estrogen Receptor alpha; D004967:Estrogens; D006657:Histones; D014157:Transcription Factors; D012319:RNA Polymerase II